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[已完成翻译] [一时兴起,胡乱翻译]How D2OL will help cure SARS

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发表于 2007-6-21 13:12:21 | 显示全部楼层 |阅读模式
随便翻译了一下,很古老的帖子,前两天在论坛看到有帖子介绍,就跑去看了看,搜了搜发现没人翻译,就自己随便翻译了一下(英语和医药知识都很薄弱),就当给自己科普了D2OL的研究过程.

原文在  http://www.d2ol.com/cgi-bin/ulti ... _topic;f=1;t=000149

这里有过转载  http://www.equn.com/forum/viewth ... amp;page=1#pid53768

想把自己的翻译发上来,但又不知道该发在哪里,也不知道有没有人会看,不过纯当兴趣,抱着与大家分享(以及接受大家指正)的态度,呵呵~

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原文

How D2OL will help cure SARS

posted May 15, 2003 05:18 PM

To all members of the D2OL community,

My name is Dr. Bonnie Gould Rothberg and I am the Medical Director of the Rothberg Institute, your D2OL host. On behalf of The Rothberg Institute, I would like to thank you for your time and efforts in helping us crunch towards a cure for SARS.

The strengths of a global community working in harmony have really been a driving force behind all areas of SARS research. The SARS epidemic was first brought to international attention in February and scientists from all over the world have been working at breakneck speeds towards getting at the heart of SARS. In fact, in less than 3 months, this international collaboration has led to the identification of the virus that causes SARS, the complete identification of its genetic code (i.e., its DNA sequence) and, most recently, identification of a key protein made by the SARS virus that, if shut down by a drug, could stop the SARS infection. The speed of this progress probably sets a new world record for scientific discovery. For those who wish to read the scientific literature on SARS, please visit www.nejm.org for the May 15th issue of the New England Journal Of Medicine and www.sciencemag.org for the genetic code of the SARS virus and the protein structure of this key target.

Amid this backdrop of breakneck discovery, you all have volunteered computer time to our D2OL effort against SARS. I would, then like to update you all of the progress on this project and inform you of the scientific strategy behind the SARS arm of D2OL.

1. Selection of a target for SARS
Since we posted our SARS target close to 4 weeks ago, folks have wanted to learn more about the target we selected and how interfering with this particular target will ultimately stop the SARS infection. A simple explanation follows.

The SARS virus is a member of the coronavirus, or crown-virus (under the microscope, they look like they wear crowns), family. And, to a large extent, all coronaviruses are related. So, while scientists are still learning about the intricacies of the SARS virus, there are 7 other coronaviruses that scientists are much more familiar with and have been, in fact, studying for over 30 years. Over the years, scientists have come to learn about many aspects of the coronavirus life cycle-facts that are common to all members of the coronavirus family. So, when we learned 4 weeks ago that the SARS virus was a coronavirus, even without having lots of knowledge about the specifics about the SARS virus we could apply basic ideas common to all coronaviruses to SARS. And that is what we did.

All coronaviruses make a protein called the "Coronavirus Main Protease" or 3CL-PRO , for short. This protein is absolutely essential for the virus to make copies of itself and spread the infection, so stopping this protein from working would very likely stop the virus. This protein is also very sexy from a drug development standpoint. Pharmaceutical companies already know how to make drugs that inhibit proteases made by viruses (e.g., ritonavir and indinavir are major components of anti-HIV drug regimens). It also turns out that the Agouron division of Pfizer has already successfully made drugs against the 3CL-PRO protein found in the virus responsible for the common cold (rhinovirus). The Coronavirus Main Proteinase is, therefore, an excellent drug target for anti-SARS therapy and why we selected this target 4 weeks ago.

2. Of Pigs and Man
As many of the techies already know, to prepare a drug target to work in a docking environment, it is essential that its X-ray crystal structure be solved. This work is typically done by expert biophysicists working in either industrial or academic labs. In order for D2OL to consider drug discovery against 3CL-PRO, we needed the coordinates for the protein as determined by X-ray crystal structure. Four weeks ago, (before the SARS virus was characterized) we were very fortunate to find that a group working in Germany had, a few years back, worked out the X-ray crystal structure for the 3CL-PRO from a coronavirus that causes diarrhea in pigs ( the transmissible gastroenteritis virus, TGEV ). Because we knew that all coronaviruses are very similar to each other, we made the basic assumption that since the 3CL-PRO was so essential for the coronavirus to work properly that the 3CL-PRO structure was likely to be very similar if not identical among all members of the coronavirus family. We had some evidence of this from the German group who, in their work from 2001, had shown that the key pieces of the 3CL-PRO protein were identical across all 7 of the coronaviruses they looked at. We thus uploaded to the community the 3CL-PRO identified from the pig coronavirus TGEV as a target that will help us find drugs against SARS. Just yesterday, the same German group that previously worked on the TGEV structure published in the journal Science (if you publish here, you are a star and you are made [Cool] ) that they solved the structure for 3CL-PRO from a coronavirus that causes a variety of the human cold (a.k.a. HCo-V) and based on this structure and that from the TGEV, they were able to deduce the structure of the SARS coronavirus 3CL-PRO. Their conclusions were as follows:
1. As per our assumption, the guts of the 3CL-PRO (the parts that make it work correctly) are the similar enough across all coronaviruses such that drugs that are useful for one type should be useful for all
2. Based on the work done by the Agouron scientists, the German team concluded that 3CL-PRO would be an outstanding target to stop SARS.

But we all already knew this 4 weeks ago [Big Grin] .

3. So what's next? .
First and foremost, at The Rothberg Institute, we are scientists. Now that we have spent our 5 minutes patting ourselves on the back for picking the right target in 3CL-PRO, we have been very carefully reading the Science paper from the German group and using it to help us put together an action plan. I would like to share that plan with you all.
A. Updating and adding more SARS targets. Now that the actual X-ray crystal structure for the 3CL-PRO from the HCo-V human coronavirus is known and the SARS version is strongly suggested, we will be adding these ASAP (should be up by the end of the month) as SARS targets II & III. By crunching all 3 flavors of the coronavirus 3CL-PRO, we should be able to identify candidate molecules that are ranked as top candidates for all 3 targets. We hope that the probability of getting a drug to score high for all 3 targets by chance alone is much less than if it is due to real chemical factors. Candidates making the tops of all 3 lists then have a better chance of owrking at the lab bench, thus speeding up our efforts.
B. Learning from Agouron/Pfizer. As I have mentioned, the scientists at Agouron have already worked extensively with the cold virus (rhinovirus) 3CL-PRO and have even made drugs that have tight binding to it. All of this has been published in the scientific literature. We would like to leverage their knowledge to help make our effort more tightly controlled. Firstly, we will also load up a 4th target, the 3CL-PRO from the rhinovirus-the same one that Agouron worked on. So don't be surprised when folks see this target as one to crunch. We are also going to load up all of the chemicals that Agouron has published that bind to the the rhinovirus 3CL-PRO and mix these up with the candidates that we already have. Then we will see if our computer can pull up the Agouron molecules as strong candidates for the rhinovirus 3CL-PRO (it should). If it does, we know for certain that our program is optimized to crunch for good targets for 3CL-PROs. If we get less than perfect results, our computational chemists on staff will be put to the task of tweaking D2OL to get a better fit between the Agouron drugs and the rhinovirus 3CL-PRO. For the non-scientists out there, this part of the experiment is called the "control" and is an essential part for any experiment. Good controls are what sets apart good science from hocus-pocus magic.

Please do look for the new changes to your D2OL client in the next few weeks. And, as always, we'll be posting updates when these changes are about to happen.

We will also be happy to respond to members of the community who may have additional questions.

Thanks,

Dr. Bonnie
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 楼主| 发表于 2007-6-21 13:13:02 | 显示全部楼层

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D2OL如何帮助治疗SARS

发表于 五月 15, 2003 17:18

致D2OL社团的所有成员,

我是Dr. Bonnie Gould Rothberg,并且我是D2OL的主办方罗斯伯格研究院(Rothberg Institute)的医学主管。我谨代表罗斯伯格研究院来向您为帮助我们治疗SARS而付出的时间和努力表示感谢。

全球的协调一致的社团工作的力量已经成为了所有地区的SARS研究的驱动力。自二月份SARS的流行引起国际上的注意以来,来自全世界的科学家们用极限的速度来工作,以期到达SARS的核心。事实上,在不到三个月的时间内,这一国际协作已经获得了辨认出导致SARS的病毒的结果,完全鉴别了病毒的遗传密码(即,它的DNA序列),以及刚刚鉴定出来的一个SARS病毒生成的关键蛋白质。如果用药物将其终止,就能够停止SARS的感染。这一研究进程的速度可能创造了科学发现的一项新的世界纪录。想阅读有关SARS的科学文献的人们,请访问 www.nejm.org 来查阅5月15日发行的New England Journal Of Medicine,以及访问 www.sciencemag.org 来获得SARS的遗传密码和那个关键蛋白质的结构。

在这次竭尽全力的探索研究的背后,你们所有人都无偿奉献了计算时间给我们D2OL来努力抗击SARS。之后我希望把项目所取得的进展全部展现给你们,并告诉你们D2OL对付SARS的科学策略。

1. 为SARS选择一个目标
自从大约四周前我们发布了我们的SARS目标以来,民众就希望更多的了解这一目标,以及想知道我们选定的这一特定目标是如何能够最终结束SARS感染的。下面将是一个简单的解释。

SARS病毒是一种冠状病毒(在显微镜下观察,它们就像带着王冠一样)。并且,在很大程度上,所有的冠状病毒都是相关的。所以,在科学家们研究错综复杂的SARS病毒的同时,他们已经对另外7种冠状病毒非常熟悉了,并且事实上已经研究了超过30年了。在这些年里,科学家已经发现了冠状病毒家族的生命周期中许多共有的方面。因而在四周前,当我们得知SARS病毒是一种冠状病毒时,即使没有多少关于SARS病毒的特定知识,我们依然可以把对待所有冠状病毒的基本观念应用到SARS病毒上。这就是我们所做的。

所有的冠状病毒都生成一种称为“冠状病毒主蛋白酶(Coronavirus Main Protease)”的蛋白质,或者简称3CL-PRO。该蛋白质正是病毒进行自我复制及传播感染的必要元素。因此阻止这种蛋白质的工作将很可能终止该病毒。从药物开发的观点来说,这种蛋白质也是非常诱人的。制药公司已经知道如何生产能够抑制病毒所产生的蛋白酶的药物(例如,ritonavir和indinavir就是抗HIV药物食物疗法的重要成分)。Agouron division of Pfizer已经成功生产了抗3CL-PRO蛋白质的药物也证实了这一点。3CL-PRO蛋白质是在导致感冒的病毒中被发现的(鼻病毒rhinovirus)。因而冠状病毒主蛋白酶是抗SARS治疗药物的一个极佳的目标。这也是我们四周前选择这一目标的原因。

2. 猪和人
如许多技术人员所知,在docking环境中准备一个药物目标来工作,解决它的X光透明结构(X-ray crystal structure)是非常必需的。这一工作的典型做法是由专门的生物物理学家在工业或学术实验室里面去完成的。为了使D2OL能够发现对抗3CL-PRO的药物,我们需要这种已经确定X光透明结构的蛋白质的配形物(coordinates)。四周前,(在SARS病毒被辨别之前)我们非常幸运的发现在德国的一个团队已经进行了几年的研究。他们计算出了导致猪腹泻(diarrhea)的冠状病毒(可遗传的肠胃炎病毒, the transmissible gastroenteritis virus, TGEV )的3CL-PRO的X光透明结构。因为我们知道所有的冠状病毒相互之间都十分相似,所以我们制定了一个基本的假设,即由于3CL-PRO是冠状病毒正常运作的基本要素,那么3CL-PRO的结构就算在整个冠状病毒家族并不完全相同,也很可能是非常相似的。我们从德国团队那里得到了一些有关于此的证据。该团队从2001年开始的工作显示3CL-PRO蛋白质的关键部分在他们所研究的7种冠状病毒中是完全相同的。因而我们把已经识别了3CL-PRO的猪致病冠状病毒TGEV也作为一个目标上传到社区。这将有助于我们找到对抗SARS的药物。就在昨天,那个德国团队之前关于TGEV结构的工作被发表在了科学杂志上(如果你在这本杂志上发表文章,你将会是一个明星,你会被认为很酷)。该团队解决了一种能够导致多种的人类感冒(也称为HCo-V)的冠状病毒的3CL-PRO的结构,并且据此以及从TGEV得到的结构,他们能够推论出SARS冠状病毒的3CL-PRO结构。他们的结论如下:
1. 在我们的假设中,3CL-PRO(能够令冠状病毒正常工作的部分)的内容在所有冠状病毒中都是足够相似的。这样一来,对某种类型有效的药物也将对所有的类型有效。
2. 基于Agouron的科学家们所做的工作,德国团队论断了3CL-PRO将会是终止SARS的一个显著的目标。

但我们四周前就已经知道了[开怀大笑]。

3. 那么下一步呢?
首先,在罗斯伯格研究院,我们是科学家。我们花了几分钟来夸耀我们选择了3CL-PRO这一正确的目标,我们还很谨慎阅读了来自德国团队的科学论文,并用其帮助我们共同完成了一个行动计划。我很高兴来把这个计划与你们所有人共同分享。
A. 更新和添加更多的SARS目标。我们已经知道了从HCo-V人致病冠状病毒的得到的3CL-PRO的实际的X光透明结构(X-ray crystal structure),并且对SARS也有了很深的了解,我们亦将尽快(应该在月底之前)添加这些内容来作为SARS目标II和III。等处理完所有三类冠状病毒的3CL-PRO,我们将会从候选分子中识别这三个目标的排位最佳的分子。我们希望,单单偶然的得到一个在三个目标中都能够获取高分的药物的几率要比考虑了现实的化学因素后的几率来的少得多。3个列表中排位最佳的候选者之后会有一个更好的机会来参与我们的实验室工作,从而加速我们的进展。
B. 向Agouron/Pfizer学习。正如我所提到的,Agouron的科学家已经对感冒病毒(鼻病毒rhinovirus)的3CL-PRO开展了广泛的工作,甚至已经制成了能够紧紧约束它的药物。所有这些已被发表在科学著作之中。我们愿借助他们的知识来帮助我们更加紧密的控制我们的成果。首先,我们还将载入第四个目标,来自鼻病毒(rhinovirus)的3CL-PRO——与Agouron正在从事的相同。因此当大家看到来处理这样一个目标时不必感到惊讶。我们还将载入Agouron所发表的所有约束rhinovirus 3CL-PRO的化学制品,并将它们与我们已获得的候选者进行混合。然后我们将会观察我们的计算机是否能挑出那些Agouron分子作为rhinovirus 3CL-PRO的强势的候选者(理应是这样的)。如果这样的话,我们就可确认,我们的程序已经被优化为适合于处理3CL-PRO的好目标。如果我们没能获得理想的结果,我们当中的计算化学家(computational chemists)将会进行调试D2OL的工作,以期在Agouron药物和rhinovirus 3CL-PRO之间得到更好的一致配合。对于那些并非科学家的人来说,这部分的试验被称为“调节控制(control)”,并且这是任何试验的一个基础部分。好的调节控制能够使好的科学与哄骗人的戏法分离开来。

在接下来的几星期里,敬请等待您的D2OL客户端的新的变化。并且我们也会一如既往的在发生变化前张贴更新信息。

我们亦将很高兴来回应社团成员的其它问题。

非常感谢,

Dr. Bonnie

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